# NM_004628.5(XPC):c.1001del (p.Pro334fs)

https://sugi.bio/variant/xpc-p-pro334fs

## Summary

**XPC p.Pro334fs (c.1001del)** is classified **Pathogenic** in XPC (ClinVar, Single submitter, 1 submitter; last evaluated 2018-12-18). Very rare (popmax 8.48e-05%, nfe).

**At a glance:** Pathogenic · review: Single submitter · rsID rs1574963068 · 1 submitter · very rare (popmax 8.48e-05%, nfe)

## For patients & families {#patients}

This is a change in the XPC gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [XPC](https://sugi.bio/atlas/gene/XPC/) |
| Protein change (HGVS p.) | p.Pro334fs |
| Coding change (HGVS c.) | c.1001del |
| MANE Select transcript | [NM_004628](https://www.ncbi.nlm.nih.gov/nuccore/NM_004628) |
| dbSNP | [rs1574963068](https://www.ncbi.nlm.nih.gov/snp/rs1574963068/) |
| Variant type | Deletion |
| Location | chr3:14158882-14158882 (GRCh38) |
| ClinVar | [VCV644990](https://www.ncbi.nlm.nih.gov/clinvar/variation/644990/) |

**All HGVS expressions:** `LRG_472:g.24791del`, `NC_000003.11:g.14200383del`, `NC_000003.12:g.14158883del`, `NG_011763.1:g.24791del`, `NM_001354726.2:c.422del`, `NM_001354727.2:c.1001del`, `NM_001354729.2:c.983del`, `NM_001354730.2:c.1001del`, `NM_004628.5:c.1001del`, `NR_148950.2:n.1034del`, `NR_148951.2:n.910del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.199, GERP -2.06 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.023, pLI 1.2517e-20. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 9 of 16**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.48e-05%** (nfe) · 1/1,179,868 in the highest group · 1/1,613,922 alleles overall — very rare (popmax 8.48e-05%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**XPC** population constraint: LOEUF 1.023, pLI 1.2517e-20, missense-Z 0.46534. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **xeroderma pigmentosum group C** — Definitive (AR)

## Protein context {#protein}

Residue **334** lies in the 'disordered' region; a UniProt-annotated variant site (in xp-c; severe; does not affect interaction with kat2a and transcription coactivator activity in absence of dna damage).

AlphaFold model confidence (whole protein): pLDDT 67.67, 40% of residues very-high.

**18 experimental structure(s)** (PDB): [28JM](https://www.rcsb.org/structure/28JM), [28JS](https://www.rcsb.org/structure/28JS), [28JV](https://www.rcsb.org/structure/28JV), [28KE](https://www.rcsb.org/structure/28KE), [2A4J](https://www.rcsb.org/structure/2A4J), [2GGM](https://www.rcsb.org/structure/2GGM).

## What this gene does {#gene-function}

*Describes the biological roles of XPC (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** XPC's established molecular role includes damaged DNA binding. p.Pro334fs falls in the disordered region.


### Pathways affected {#pathways}

XPC participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [DNA Damage Recognition in GG-NER](https://reactome.org/content/detail/R-HSA-5696394) | curated |
| [Formation of Incision Complex in GG-NER](https://reactome.org/content/detail/R-HSA-5696395) | curated |
| [SUMOylation of DNA damage response and repair proteins](https://reactome.org/content/detail/R-HSA-3108214) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** damaged DNA binding, single-stranded DNA binding, transcription coactivator activity, protein-containing complex binding, DNA damage sensor activity.

**Biological process:** nucleotide-excision repair, positive regulation of DNA-templated transcription, UV-damage excision repair, regulation of mitotic cell cycle phase transition.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-12-18.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2018-12-18 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related XPC variant pages (same residue, condition, or type): [XPC p.Pro334His](/variant/xpc-p-pro334his), [XPC p.Pro334Ser](/variant/xpc-p-pro334ser), [XPC p.Pro334Leu](/variant/xpc-p-pro334leu), [XPC p.Ala674fs](/variant/xpc-p-ala674fs), [XPC p.Arg314fs](/variant/xpc-p-arg314fs), [XPC p.Arg423fs](/variant/xpc-p-arg423fs), [XPC p.Asp121fs](/variant/xpc-p-asp121fs), [XPC p.Gln368fs](/variant/xpc-p-gln368fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 644990). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*